RT Journal Article
SR Electronic
T1 Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.10.941393
DO 10.1101/2020.02.10.941393
A1 Sonia Moreno-Grau
A1 Maria Victoria Fernández
A1 Itziar de Rojas
A1 Isabel Hernández
A1 Fabiana Farias
A1 John P Budde
A1 Inés Quintela
A1 Laura Madrid
A1 Antonio González-Perez
A1 Laura Montrreal
A1 Pablo Garcia-Gonzalez
A1 Emilio Alarcón-Martín
A1 Montserrat Alegret
A1 Olalla Maroñas
A1 Juan Antonio Pineda
A1 Juan Macías
A1 GR@ACE & DEGESCO consortia
A1 Alzheimer’s Disease Neuroimaging Initiative
A1 Marta Marquié
A1 Sergi Valero
A1 Alba Benaque
A1 Jordi Clarimón
A1 Maria Jesus Bullido
A1 Guillermo García-Ribas
A1 Pau Pástor
A1 Pascual Sánchez-Juan
A1 Victoria Álvarez
A1 Gerard Piñol-Ripoll
A1 Jose María García-Alberca
A1 José Luis Royo
A1 Emilio Franco-Macías
A1 Pablo Mir
A1 Miguel Calero
A1 Miguel Medina
A1 Alberto Rábano
A1 Jesús Ávila
A1 Carmen Antúnez
A1 Luis Miguel Real
A1 Adelina Orellana
A1 Ángel Carracedo
A1 María Eugenia Sáez
A1 Lluis Tárraga
A1 Mercè Boada
A1 Carlos Cruchaga
A1 Agustín Ruiz
YR 2020
UL http://biorxiv.org/content/early/2020/02/11/2020.02.10.941393.abstract
AB Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [βFROH (CI95%) = 0.051 (0.023 – 0.078); P = 3.25 x 10-4]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10-16). The top associated ROH with AD risk (β (CI95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 x 10-4) was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.